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Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes (KML002)

Primary Purpose

Diabetes Mellitus, Type 1, Endothelial Dysfunction

Status
Not yet recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dulaglutide
Placebo
exercise training
Sponsored by
University of Virginia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 1 focused on measuring microvessels, oxidative stress, Dulaglutide, Glucagon-like peptide-1, Exercise therapy

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • History of type 1 diabetes, duration > 5 years
  • Age 18-40 years
  • HbA1c < 8.5%
  • BMI 19-27 kg/m2
  • Using insulin for diabetes treatment only (multiple daily injections or insulin pump with or without sensor augmentation)
  • On stable regimen of non-diabetic medications for the last 6 months
  • All screening labs within normal limits or not clinically significant
  • C-peptide <0.6 ng/ml
  • Performing less than 150 minutes of moderate intensity physical activity or less than 70 minutes of high intensity physical activity per week (i.e. achieving less physical activity than recommended by the American Diabetes Association)

Exclusion criteria:

  • Pregnancy or currently breastfeeding
  • Smoking history within 6 months
  • History of microvascular (microalbuminuria, retinopathy, neuropathy) or macrovascular diabetes complications (coronary artery disease, stroke, peripheral vascular disease) as well as clinically significant cardiac arrhythmias or conduction disorders
  • Taking vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha-blockers).
  • Known hypersensitivity to perflutren (contained in Definity© contrast)
  • Screening O2 saturation <90%
  • Musculoskeletal condition preventing participation in exercise testing or exercise training
  • Acute or unstable disease other than T1D
  • Hypoglycemia unawareness (based on Clarke's questionnaire)
  • History of gastroparesis, severe gastroesophageal reflux, pancreatitis, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2
  • Anemia (hemoglobin <12 g/dL in women, hemoglobin <13 g/dL in men), eosinophilia (absolute eosinophil count >500 cells/microliter) leukopenia (total white blood cells <4,000 cells/microliter)
  • Diabetic ketoacidosis (DKA) on presentation to screening visits or study admission days
  • Hospital admission for DKA within 1 year

Sites / Locations

  • University of Virginia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Arm Label

Placebo

Dulaglutide

Exercise training

Arm Description

Saline subcutaneous injection, volume matched to dulaglutide, i.e. 0.5 mL weekly for 14 weeks

Dulaglutide (0.75 mg/0.5 mL weekly for 2 weeks, then 1.5 mg/0.5 mL weekly for 12 weeks) subcutaneous injection

Supervised high intensity interval training on a stationary bicycle will be conducted 3 days per week for 14 weeks. Participants will warm up at low intensity for 3 min then repeat 1-min bouts of 100% peak power output followed by 1-min recovery at 50 W. Training will start with 6 intervals per session, increasing by 2 intervals every 2 weeks. Sessions will end with a 10-min cool-down.

Outcomes

Primary Outcome Measures

Microvascular blood volume (MBV)
Insulin mediated change in muscle microvascular blood volume (MBV). A measure of microvascular nitric oxide dependent endothelial function

Secondary Outcome Measures

Brachial artery flow mediated dilation (FMD)
Post-occlusive percent (%) change in diameter. A measure of conduit artery nitric oxide-dependent endothelial function.
Glucose infusion rate (GIR)
Mean GIR over the final 30 minutes of euglycemic insulin clamp; a measure of insulin sensitivity
Cardiorespiratory fitness, maximum consumption of oxygen (VO2max)
Assessed by cycle ergometer exercise testing.
Skeletal muscle oxygenation, deoxyhemoglobin (HHb)
Assessed by frequency domain multi-distance near-infrared spectroscopy (NIRS) monitor at the quadriceps muscle

Full Information

First Posted
July 25, 2022
Last Updated
October 31, 2022
Sponsor
University of Virginia
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1. Study Identification

Unique Protocol Identification Number
NCT05478707
Brief Title
Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes
Acronym
KML002
Official Title
Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 2022 (Anticipated)
Primary Completion Date
June 2027 (Anticipated)
Study Completion Date
June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Virginia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The investigators will test the hypothesis that, in adults with type 1 diabetes (T1D), glucagon-like peptide-1 receptor agonism (GLP-1RA, i.e. dulaglutide) and exercise training each enhance insulin-mediated skeletal muscle microvascular perfusion via attenuating endothelial oxidative stress and thereby improving endothelial function.
Detailed Description
In this study, 64 (n=42 needed to complete) adult participants with type 1 diabetes will be randomized (1:1:1) to 14-weeks of one of 3 interventions: 1) dulaglutide, 2) placebo, or 3) exercise training. Participants will undergo two study admissions at baseline and 14 weeks. Prior to each admission, participants will wear a continuous glucose monitor (Dexcom G6 Professional) for 10 days to assess glycemic variability (GV). Prior to admissions, they will undergo cardiorespiratory fitness testing. On study admission days, participants will undergo an antecubital vein endothelial cell biopsy prior to commencing vascular testing. From the harvested endothelial cells, the investigators will quantify endothelial cell reactive oxygen species (ROS) and protein expression relevant to insulin-mediated endothelial function. Vascular testing will include contrast enhanced ultrasound of quadriceps muscle to determine microvascular blood volume (MBV). The investigators will also measure brachial artery flow mediated dilation (FMD). Quadriceps skeletal muscle oxygenation (HHb) will also be measured. These vascular and muscle oxygenation measurements will be conducted before and after a 120-minute euglycemic insulin clamp which will measure insulin sensitivity based on glucose infusion rate (GIR). This randomized, placebo-controlled study will assess whether GLP-1 receptor agonism with dulaglutide or exercise training improves insulin-mediated skeletal muscle microvascular perfusion. The investigators will assess for predictive relationships between microvascular perfusion and cardiorespiratory fitness (VO2max), insulin sensitivity (GIR), endothelial reactive oxygen species (ROS), and glycemic variability (GV).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1, Endothelial Dysfunction
Keywords
microvessels, oxidative stress, Dulaglutide, Glucagon-like peptide-1, Exercise therapy

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Masking Description
Participants randomized to dulaglutide or placebo and study personnel who analyze data and instruct patients regarding insulin adjustments will be blinded to treatment allocation.
Allocation
Randomized
Enrollment
64 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Saline subcutaneous injection, volume matched to dulaglutide, i.e. 0.5 mL weekly for 14 weeks
Arm Title
Dulaglutide
Arm Type
Active Comparator
Arm Description
Dulaglutide (0.75 mg/0.5 mL weekly for 2 weeks, then 1.5 mg/0.5 mL weekly for 12 weeks) subcutaneous injection
Arm Title
Exercise training
Arm Type
Active Comparator
Arm Description
Supervised high intensity interval training on a stationary bicycle will be conducted 3 days per week for 14 weeks. Participants will warm up at low intensity for 3 min then repeat 1-min bouts of 100% peak power output followed by 1-min recovery at 50 W. Training will start with 6 intervals per session, increasing by 2 intervals every 2 weeks. Sessions will end with a 10-min cool-down.
Intervention Type
Drug
Intervention Name(s)
Dulaglutide
Intervention Description
GLP1-RA
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Saline placebo
Intervention Type
Behavioral
Intervention Name(s)
exercise training
Intervention Description
supervised high intensity interval training
Primary Outcome Measure Information:
Title
Microvascular blood volume (MBV)
Description
Insulin mediated change in muscle microvascular blood volume (MBV). A measure of microvascular nitric oxide dependent endothelial function
Time Frame
At baseline and after 14 weeks of treatment.
Secondary Outcome Measure Information:
Title
Brachial artery flow mediated dilation (FMD)
Description
Post-occlusive percent (%) change in diameter. A measure of conduit artery nitric oxide-dependent endothelial function.
Time Frame
At baseline and after 14 weeks of treatment
Title
Glucose infusion rate (GIR)
Description
Mean GIR over the final 30 minutes of euglycemic insulin clamp; a measure of insulin sensitivity
Time Frame
At baseline and after 14 weeks of treatment
Title
Cardiorespiratory fitness, maximum consumption of oxygen (VO2max)
Description
Assessed by cycle ergometer exercise testing.
Time Frame
At baseline and after 14 weeks of treatment
Title
Skeletal muscle oxygenation, deoxyhemoglobin (HHb)
Description
Assessed by frequency domain multi-distance near-infrared spectroscopy (NIRS) monitor at the quadriceps muscle
Time Frame
At baseline and after 14 weeks of treatment. Measured before and after insulin clamp.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: History of type 1 diabetes, duration > 5 years Age 18-40 years HbA1c < 8.5% BMI 19-27 kg/m2 Using insulin for diabetes treatment only (multiple daily injections or insulin pump with or without sensor augmentation) On stable regimen of non-diabetic medications for the last 6 months All screening labs within normal limits or not clinically significant C-peptide <0.6 ng/ml Performing less than 150 minutes of moderate intensity physical activity or less than 70 minutes of high intensity physical activity per week (i.e. achieving less physical activity than recommended by the American Diabetes Association) Exclusion criteria: Pregnancy or currently breastfeeding Smoking history within 6 months History of microvascular (microalbuminuria, retinopathy, neuropathy) or macrovascular diabetes complications (coronary artery disease, stroke, peripheral vascular disease) as well as clinically significant cardiac arrhythmias or conduction disorders Taking vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha-blockers). Known hypersensitivity to perflutren (contained in Definity© contrast) Screening O2 saturation <90% Musculoskeletal condition preventing participation in exercise testing or exercise training Acute or unstable disease other than T1D Hypoglycemia unawareness (based on Clarke's questionnaire) History of gastroparesis, severe gastroesophageal reflux, pancreatitis, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 Anemia (hemoglobin <12 g/dL in women, hemoglobin <13 g/dL in men), eosinophilia (absolute eosinophil count >500 cells/microliter) leukopenia (total white blood cells <4,000 cells/microliter) Diabetic ketoacidosis (DKA) on presentation to screening visits or study admission days Hospital admission for DKA within 1 year
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kaitlin Love, MD
Phone
434-924-9651
Email
KML2W@hscmail.mcc.virginia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Lee Hartline, MEd
Email
lmh9d@virginia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kaitlin Love, MD
Organizational Affiliation
Associate Professor - Endocrinology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaitlin Love, MD
Email
KML2W@hscmail.mcc.virginia.edu

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Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

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